The present invention relates to multi-unit sustained-release pharmaceutical preparations and the method for making them. More particularly, it relates to microparticles formed of granular drug soluble in digestive fluids, which drug is coated with a multi-wall structure to give a delayed and sustained drug delivery. The microparticles of multi-walled coated drug may be mixed or concentrically coated with immediate release drug and/or single walled coated drug to provide an improved sustained-release system.
As is well known, the maximum time of effectiveness in many pharmaceutical preparations, particularly those containing a drug such as aspirin, acetaminophen, indomethacin, propranolol hydrochloride, dextromethorphan, etc. is only a few hours because of biological modification and/or elimination of the medication in the body. Consequently, repeated dosages must be taken at frequent intervals to obtain long term therapeutic levels of drug. Furthermore, these drugs usually dissolve readily in the digestive juices and the total dosage is immediately fed into the blood stream. After high initial peak concentrations, the level of drug in the blood stream constantly decreases because of the biological elimination, so there is little or no therapeutic effect at the end of the period between dosages. As a result, the therapeutic effect fluctuates between dosages corresponding to the peaks and valleys in the level of drug in the blood as commonly measured by trough to peak ratios.
Many attempts have been made to develop timed-released pharmaceutical preparations which provide a more constant level of the drug in the blood over several hours.
One common approach is to microencapsulate aspirin, for example, with a capsule wall material which provides a slower dissolution rate than free aspirin. The early work in that regard is represented by U.S. Pat. Nos. 3,155,590; 3,341,416; 3,488,418, and 3,531,418. Those patents, among others, disclose dispersing particles of aspirin in a hot cyclohexane solution containing ethyl cellulose and then introducing a phase-separation inducing agent, such as butyl rubber or polyethylene. Upon cooling, the aspirin particles become coated with ethyl cellulose. The coated particles are then admixed with tableting excipients and formed into dosage-sized tablets. When ingested, the tablets disintegrate rapidly and the individual particles of encapsulated aspirin are dispersed in the stomach. The gastric juices slowly diffuse through the capsule walls, dissolve the aspirin, and the dissolved aspirin slowly diffuses or leaches out through the capsule walls into the body. Although the resultant blood level content is sustained to a measurable extent, the aspirin is diffused into the body rapidly enough so there is an initially high blood level content which decreases quite rapidly within a few hours. These dissolution properties yield undesirable blood aspirin concentration versus time curves.
In the first place, the time required to reach therapeutic levels after ingestion is longer for timed-release aspirin than for free aspirin. For this reason, it has been proposed that free aspirin be tableted with coated aspirin particles. See, for example, U.S. Pat. No. 3,115,441 which discloses mixing aspirin particles having a series of coatings thereon with uncoated aspirin, and tableting so that the coated particles are entrapped in uncoated aspirin. Tablets made according to the method have the advantage of providing immediate relief because the free aspirin (which comprises the initial dosage) dissolves immediately upon ingestion. However, as with the other preparations discussed above, the tablet rapidly disintegrates in the stomach.
See also Guy U.S. Pat. No. 4,025,613 where a multi-layered tablet is disclosed. One layer comprises aspirin coated with cellulose acetate phthalate and the other layer is free aspirin. However, as stated in Dunn, U.S. Pat. No. 4,520,009, while aspirin tablets prepared by the process of Guy exhibit desirable in vitro release properties, processing difficulties are encountered in production runs. Dunn, then, is said to be an improvement in that large batch processing is allegedly made easier. In Dunn an admixture of aspirin, microcrystalline cellulose, cellulose acetate phthalate, plasticizer, corn starch and lubricant is compressed into tablet form. There is no microencapsulation as such in Dunn and, accordingly, the advantages of multi-units dosage of microencapsulated particles are foregone in favor of processing ease.
With microencapsulated particles, as discussed above, the dissolution rate decreases rapidly and the blood aspirin concentration at 2-3 hours must greatly exceed the therapeutic level in order to maintain adequate aspirin concentrations at 8 hours. As a result, efforts have been made to adjust the rate of dissolution and, thus, control the timing of sustained drug release. See, for example, Peters U.S. Pat. No. 3,492,397 where the dissolution rate is said to be controlled by adjusting the wax/ethyl cellulose ratio of the applied spray coating, and Metha, U.S. Pat. No. 4,752,470 where the controlled release characteristics for indomethacin are varied depending on the ratio of ethyl cellulose to hydroxypropyl cellulose in the coating. See also U.S. Pat. Nos. 4,205,060 and 3,488,418 where it is indicated that the rate of dissolution of various drugs can be controlled by varying the thickness of the coating applied to those drugs.
Thus, not only aspirin, but other drugs soluble in digestive fluids have been treated or compounded in an effort to achieve a more controlled release of the drug in the digestive system. As mentioned, many of those attempts have involved encapsulation processes.
Another method for providing an encapsulated pharmaceutical composition is discussed in published European Patent Application No. 77,956, published May 4. 1983. EPO Publication No. 77,956 discloses the use of microcapsules containing a coated core material such as pharmaceutical compounds and foodstuffs. The coating is applied by dispersing the core material into a solution containing ethyl cellulose as the wall-forming material. A phase separation of the ethyl cellulose from the dispersion of core material is carried out by cooling the dispersion. During this cooling, an enteric polymer material is incorporated into the ethyl cellulose coating walls by adding the enteric polymer material with stirring while the ethyl cellulose is still in the "gel" state. The enteric polymer material thus added penetrates and is dispersed into the coating walls. When the microcapsules are administered, the release of the active compound does not generally occur in the stomach. However, the enteric polymer material is easily dissolved in the intestinal tract, thereby making the microcapsules porous. The porosity of the microcapsules promotes the rapid release of the active compound in the intestinal tract.
A similar approach is found in Japanese Patent publication No. 12614/81. published Mar. 23, 1981. Japanese Publication No. 12614/81 discloses an enteric protective coating composition which will not readily dissolve in acidic gastic juices, but rapidly (within minutes) dissolves at the pH found in the intestines. The enteric coating is an aqueous dispersion of, for example. hydroxy propyl methyl cellulose phthalate, a gelling agent such as diacetin, and hydroxy propyl methyl cellulose. See, also, Japanese Patent Publication No. 11687/81. published Mar. 16, 1981. which uses hydroxy propyl methyl cellulose phthalate as an enteric coating.
The systems described in the EPO and Japanese publications are essentially "delayed" release mechanisms. There is a delay of medicament release in the stomach, but once the coated medicament reaches the intestines, the release of medication is rapid. There is no sustained release of medication in the intestines.
Still other systems for encapsulating or coating pharmaceutical preparations are known. For example, Lehmann et al, Practical Course in Lacquer Coating (Rohm Pharma) discuss possible combinations of coating agents. Lehmann et al suggests using a multi-layered dragee design to achieve the desired release profile. Lehmann et al disclose using mixtures of EUDRAGIT acrylic resin retard coatings and lacquer substances that are resistant to gastric juices when the aim is to modify the release pattern. However, Lehmann et al do not disclose or suggest any specific formulations or guidelines for acheving a desired release profile.
Note should be made of Mehta et al, U.S. Pat. No. 4,728,512 which discloses using three distinct release formulations. The preparation consists of three groups of spheroids containing active medicinal substance. The first group of spheroids is uncoated and rapidly disintegrates upon ingestion to release an initial dose of medicinal substance, then a second group of spheroids is coated with a pH sensitive coat to provide a second dose, and finally a third group of spheroids is coated with a pH independent coat to provide a third dose. Metha et al use three distinct spheroids encapsulated in a capsule dosage rather than a single microencapsulated spheroid formulation. Consequently, the result is three distinct releases at different times rather than a uniform sustained release. Furthermore, there is very limited flexibility in achieving various release profiles when using this formulation.
Finally, reference is made to applicants' copending application Ser. No. 017.988, filed Feb. 24, 1987, the disclosure of which is hereby incorporated by reference. In the copending application there is disclosed a sustained-release pharmaceutical preparation comprising a dual walled coated drug having an inner wall microencapsular control coating, such as ethyl cellulose, and an outer wall enteric coating, such as cellulose acetate phthalate. Such a dual-walled material will release less than 10% per hour of core drug while in the stomach but will slowly release the core drug in the intestines to provide adequate drug levels for 8 or more hours. While this represents an improved result, a system which provides a longer delay in dissolution of drug from the slow release component would provide greater flexibility in designing sustained release profiles, especially for once-a-day sustained release formulations for a wide variety of drugs.
Accordingly, the need exists for a further improved sustained-release pharmaceutical preparation which has an extended dosing interval, provides more constant blood concentration levels, is economically produced, and has the advantages of a multi-units formulation.